New basically substituted acridine compounds



Patented June 21, 1938 UNITED STATES PATENT @FFEQE NEW BASIOALLYSUBSTITUTED ACRIDHNE COMPOUNDS N Drawing.

Application .l'une 3, 1935, Serial No. 24,775. In Germany June 7, 1934Claims.

This invention relates to new basically substituted acridine compoundsand is a further development of the invention described and claimed inour co-pending application for Letters Patent Ser. No. 534,460, filedMay 1, i931, and Ser. No. 726,866, filed May 21, 1934. The new acridinecompounds same as the acridine compounds described in the said(so-pending applications are distinguished by a considerable eflicacy onblood parasites.

In accordance with the present invention the new acridine compoundsdisplaying the said anti-parasitic properties particularly againstmalaria parasites are obtainable by the manufacture of acridinecompounds of the general formula:

in which R stands for hydrogen or alkyl, such as methyl or ethyl, Rstands for an aliphatic radical, such as a methylene, ethylene,propylene,

hydroxypropylene group, or for alkylene groups which are interrupted byether-like bound oxy gen or sulfur atoms, and R and R stand for alkyl,alkoxy or alkylthio groups, such as the methyl, ethyl, butyl, methoxy,lSODI'QpYlOX, hydroxypropyloxy, methylthio, ethylthio group and thelike. The saidalkyl, alkoxy and alkylthio groups in the 2- and7-position of the new acridine compounds have proved to be of essentialimportance as to the anti-parasitic properties of the new products andare equivalent in this respect.

In accordance with the present invention the said new acridine compoundsare prepared by reactingupon such acridine substitution products ascontain in the 9-position a replaceable subsituent and in the 2- and7-position an alkyl, alkoXy or alkylthio group, with aliphaticpolyamines containing a primary or secondary amino group. Replaceablesubstituents in the 9-position are, for instance, ether and ester likegroups, such as halogen, aryloxy, alkoxy, aryland alkylmercapto groups;The reaction is preferably carried out in phenolic solution whileheating, advantageously on the water-bath. Also other organicsubstances, containing hydroxyl or sulfhydryl groups, have proved to besuitable solvents, for instance, ethyl alcohol, glycol, amyl alcohol,cresol, naphthol, thiophenol, and the like. The reaction temperature isadvantageously at about 130 C. when using these substances as solvents.If necessary the reaction is performed in closed vessels. Presumablywhen using the 9- halogen derivatives as starting materials the reactionsometimes takes place with the formation of acridines, containing theradical of the solvent used in etheror thioether-like linkage in the9-position, as intermediate products. The reac tion is complete afterheating for about one to several hours. The new base formed may be separated off by rendering the reaction mixture alkaline and taking up thebase precipitated in an organic solvent, such as ether, methylenechloride or the like.

The aliphatic polyamine containing a primary or secondary amino groupmay contain substituents, for example, the hydrcxyl group and etherorthioether-like linkages. Suitable amines are, for instance,diethylaminoethylmethylamine, dimethylaminoethylamine,l-diethylamino-Z-hydroxypropyl 3 ethylamine, 1 diethylamino4-pentylamine, diethylaminoethylthio-propylamine,dimethylaminoethoxy-ethylamine, and the like.

The new acridine compounds are in the form of the free bases lightyellow substances which are soluble in the usual organic solvents, forexample, ether, alcohol, acetone, benzene and methylene chloride. Theymay be dissolved in water in the form of their salts with acids, such ashydrochloric, hydrobromic, sulfuric, acetic, citric, tartaric, lacticacid and the like. These salts are obtained in the customary manner byneutralizing the free base with the acid. Two equivalents of the acidneutralize one mol. of the base. Of course, the free bases are solublein dilute mineral acids and organic acid with the formation of thewater-soluble salts.

The invention is further illustrated by the following examples withoutbeing restricted thereto:-

Example 1.2l.4 grams of 2.7-dimethoxy-9- chloro-acri-dine are melted inthe Water-bath with 100 grams of phenol and 16 grams of udiethylaminodelta aminopentane are added While stirring and heating for 1 hour to90100 C. The reaction mixture is then introduced into 1009 cos. of2-normal caustic soda solution and the tylaminoacridine formed is takenup in ether. It is purified by way of its acetic acid salt and separatedas yellow dihy-drochloride which is readily soluble in water anddecomposes at 245-250" C.

The 2.T-dimethoxy-9-chloroacridine (yielding yellow crystals frombenzene, which melt at 228- 2.l-dimethoxy-9-a-diethylamino-delta-pen-229 C.) is obtained from the 4.4'-dimethoxydiphenylamine-6-carboxylicacid (yielding yellow crystals from alcohol, melting at 167-168 C.) bysubjecting it to ring closure and chlorination.

The dihydrochlorides of2.7-dimethoxy9-(edimethyl-amino-fi-ethylamino)-acridine,2.7--dimethoxy-9-(a-diallylaminowproplyamino) acridine,2.7-dimethoxy-9-(a-diethylamino-deltabutylamiho)-acridine, are obtainedin the form of yellow crystal powders when using in the above exampleinstead of a-diethylamino-deltaaminopentane a dimethyl amino ,6aminoethane, a-diallylamlno -aminopropane, a-diethylamino-delta-aminobutane, respectively. Their properties correspond tothose of the above de scribed dihydrochloride.

When using a-diethylaminoethylthio-' -aminopropane (boiling at 135-136C. under 12 mm. pressure), or dimethyl-aminoethoXy-p-aminoethane(boiling at 88-92 C. under 11 mm. pressure) the dihydrochlorides of2.7-dimethoXy-9- (a diethylaminoethylthio 'y propylamino) -acri dine,and of 2.7-dimethoxy-9-(or-dimethylaminoethoxy-e-ethylamino) -acridineare obtained in the form of yellow crystals which are-soluble in water.

Instead of the dihydrochlorides the salts with other acids, forinstance, hydrobromic acid, sulfuric acid, nitric acid, acetic, lactic,tartaric acid and the like may be prepared in an analogous manner.

Example 2.33.1 grams of 2.7-dimethoxy-9- phenoxy-acridine are treatedwith 15 grams of a-diethylamino-c-hydroXy- -aminopropane in accordancewith the directions indicated in Ex ample 1. The dihydrochloride of the2.7-dimethoxy-9- (a-diethylamino hydroXy-'y-propylamino)-acridine isobtained as yellow dihydrochloride which is readily soluble in waterwith yellow ish-green fluorescence and decomposes at 240 C.

Also the dihydrobromide, the sulfate and the dinitrate are readilysoluble in water.

The 2.7-dimethoxy-Q-phenoxyacridine prepared from2.7-dimethoxy-9-ch1oroacridine by treatment with phenol, the twocomponents being melted at water-bath temperature, crystallizes fromalcohol in thin leaflets melting at MHZ-148 C. Its hydrochloride formsyellowglittering leaflets which are difiicultly soluble in water anddecompose at 225 C.

Example 3.--On treating 2-isopropyloxy-'7- methoxy-Q-chloroacridine witha-diethylamino delta-aminopentane the2-isopropyloxy-7-methoxy-9-(a-diethylamino-de1ta-pentylamino) acridineis obtained. It is isolated as a yellow citrate which is readily solublein water with yellowishgreen fluorescence.

From 4 methoxy 4' isopropyloxydiphenylamine-G-carboxylic acid (yieldingthin yellow needles from ligroin, melting at 156-15'7 C.) the 2-isopropyloxy-7-methoXy-9-chloroacridine (yielding yellow crystals fromligroin, melting at 129- 130 C.) is obtained by subjecting the formerproduct to ring closure and chlorination.

Example 4.On treating 2-methylmercapto-7- methoxy-Q-chloroacridine witha-diethylaminodelta-aminopentane the Z-methylmercapto-lmethoxy-9-(a-diethylamino-delta-pentylamino) acridine is obtained which as citrateor tartrate forms a deep-yellow colored powder which is readily solublein water.

From the 4-methoxy-4-methylmercapto-diphenylamine-G-carboxylic acid(from, alcohol yolk-like colored needles melting at 175-17 6 C.)

the 2-1nethylmercapto-'l-methoxy-Q-chloro-acridine (from benzeneyolk-like colored needles melting at 181-183 C.) is obtained bysubjecting the former to ring closure and chlorination.

The 2-butylmercapto-'l-methoxy-9-chloroacridine is prepared in ananalogous manner. When reacting thereupon with a-diethylamino-deltaaminopentane the Z-butylmercapto-l-methoxy-9-(a-diethylamino-deltapentylamino) acridine is obtained. It forms alactate which is readily soluble in water.

Example 5.The 2-methyl-7-methoxy-9-(adiethylamino-delta-pentylamino-acridine is obtained from 2-methyl-'7methoxy-9-chloroacridine anda-diethylamino-delta--amino-pentane. It forms a citric acid salt whichis readily soluble in water with yellowish-green fluorescence.

The 2-methyl-7 niethoxy 9 chloroacridine (from ligroin pale-yellowneedles melting at 161- 162 C.) is obtained from the4-methyl-4-methoXydiphenylamine-ti-carboxylic acid (from alcohol yellowprisms melting at 160-161 C.) by subjecting the latter to ring closureand chlorination.

The 2-ethyl-7-methoxy-9-ch1oroacridine is prepared in an analogousmanner. When reacted with a-diethylamino-delta-aminopentane it istransformed into the2-ethyl-7-methoxy-9-(adiethylamino-delta-pentylamino)-acridine. It isreadily soluble in water in the form of its salts, for instance, withlactic, citric and tartaric acid.

Example 6.The 2.7-dimethyl-9-(or-diethylamino-delta-pentylamino)-acridine is obtained from2.7-dimethyl-9-chloroacridine and a-diethylamino-delta-aminopentane. Itsyellow dihydrochloride is readily soluble in water and melts at 245-250C. with decomposition.

The 2.7-dimethyl-9-chloroacridine (from ligroin pale-yellow crystalpowder melting at 154-155" C.) is obtained from4.4'-dimethyldiphenylamine-6-carboxylic acid (from alcohol or benzeneyellowish crystals melting at 187-188 C.) by subjecting it to ringclosure and chlorination.

Example 7.-The 2.7-dimethyl-9-(a-diethylamino-54%dimethyl-'-propylamino) -acridine is obtained from 2.7-dimethyl9-chloroacridineand adiethylamino-fl.fldimethyl v aminopropane. Its dihydrochloridedecomposes at 238-240 C.

Example 8.From 2-n-butyloxy-7-methoxy-9- chloroacridine anda-diethylamino-s-aminopentane the 2-n-butyloxy-7-methoxy9(a-diethylamino-delta-pentylamino)-acridine is obtained in accordancewith the methods indicated in Example 1. It yields a citric acid saltwhich is soluble in water with yellowish-green fluorescence anddecomposes with foaming at C.

In an analogous manner the 2-n-butyloxy-7- methoxy-9-.(a-diethylamino-p-hydroxy 'y propylamino)-acridine is obtained from2-n-butyloxy-l-methoxy-9-chloroacridine anda-diethylamino-,e-hydroxy-v-aminopropane. Its hydrochloric acid saltmelts at 201-202 C.

The 2-n-butyloxy-7methoxy-9-chloroacridme (from ligroin thin, yellowneedles melting at 133 C.) is obtained from4-methoxy-4'-n-butyloxy-diphenylamine-fi-carboxylic acid (from alcoholyellow crystals melting at -131 C.) by subjecting it to ring closure andchlorination.

Example 9.-By reacting the Z-n-butyloxy-lethoxy-9-chloroacridine witha-diethylaminodelta-aminopentane in the above described manner the2-n-butyloxy-7-ethoxy-9-(u-diethylamino-delta-pentylamino) -acridine isobtained. It forms as citric acid salt a yellow powder which is readilysoluble in Water.

The Z-n-butyloxy-l-ethoxy-Q- (or-diethylaminop-hydroxy 7 propylamino)acridine, obtained when using a-diethylamino-,3-hydroxy-y-aminopropaneand the 9-chloroacridine compound referred to above, yields a yellowhydrochloric acid salt melting at 230-231 C.

The 2-n-butyloxy-7 ethoxy 9 chloroacridine (from benzene white,crystalline powder melting at 147 C.) is obtained from4-ethoxy-4-n-butyloxydiphenylamine-6-carboxylic acid (from alcoholyellowish-green crystals melting at 136-137 C.) by subjecting it to ringclosure and chlorination.

Example 10.'I'he 2-n-hexyloxy-7-methoxy-9-(u-diethylamino-delta-pentylamino) acridine is obtained from2-n-hexyloxy-7-methoxy-9-chloroacridine anda-diethylamino-delta-aminopentane in accordance with the methodsindicated in Example 1. It is isolated as a citric acid salt which isreadily soluble in water.

The 2-n-hexyloxy-7-methoxy-9-(u-diethylamino-5-hydroxy-y-propylamino)-acridine is obtained whenreacting a-diethylamino-p-hydroxy- 'y-aminopropane with2-n-hexyloxy-7-methoxy- Q-chloroacridine. Its yellow hydrochloric acidsalt melts at 189-190 C. while decomposing.

The 2-n-hexyloxy-7-methoxy-9-chloroacridine is obtained asyellowish-green powder melting at '74-75 C. after subjecting the4-methoxy-4'-nhexyloxydiphenylamine-G-carboxylic acid (from ligroinyellow scales melting at 102-103 C.) to ring closure and chlorination.

We claim:-

1. Acrldine compounds of the general formula:

HN'R '-N(alkyl)2 wherein R stands for an aliphatic radical and R and Reach stand for a substituent of the group consisting of the alkyl,alkoxy and alkylthio groups, which compounds in the form of the freebases are soluble in organic solvents and in the form of their saltswith acids are soluble in water.

2. Acridine compounds of the general formula:

wherein R and R each stand for a substituent of the group consisting ofthe alkyl, alkoxy and alkylthio groups, which compounds in the form ofthe free bases are soluble in organic solvents and in the form of theirsalts with acids are soluble in water.

3. Acridine compounds of the general formula:

wherein R. stands for an aliphatic radical, and R stands for asubstituent of the group consisting of the alkyl, alkoxy and alkylthiogroups, which compounds in the form of the free bases are soluble inorganic solvents and in the form of their salts with acids are solublein water.

4. Acridine compounds of the general formula:

R 0--alkyl wherein R stands for a substituent of the group consisting ofthe alkyl, alkoxy and alkylthio groups, which compounds in the form ofthe free bases are soluble in organic solvents and in the form of theirsalts with acids are soluble in water.

5. Acridine compounds of the general formula:

wherein R. stands for an aliphatic radical, which compounds in the formof the free bases are soluble in organic solvents and in the form oftheir salts with acids are soluble in'water.

6. Compounds of the group consisting of the2.7-dialkoxy-9-dialkylaminoalkylamlno-acridines and. their salts, whichcompounds in the form of the free bases are soluble in organic solventsand in the form of their salts with acids are soluble in water.

7. Compounds of the group consisting of the 2.7-dialkoxy-Q-diethylaminoalkylamino-acridines and their salts, whichcompounds in the form of the free bases are soluble in organic solventsand in the form of their salts with acids are soluble in water.

8. Compounds of the group consisting of the 2.7-dialkoxy- 9 (adiethylamino delta pentylamino) -acridines and their salts, whichcompounds in the form of the free bases are soluble in organic solventsand in the form of their salts with acids are soluble in water.

9. 2.7-dimethoxy-9-(u-diethylamino-delta-pentylamino) -acridine, whichcompound in the form of the free base is soluble in organic solvents andin the form of its salts with acids is soluble in water.

101. 2.7 dimethoxy 9 (a diethylamino -.-deltapentylamino) acridinedihydrochloride which forms a water-soluble yellow crystal powderdecomposing at 245-250 C.

FRITZ MIETZSCH. HANS MAUSS.

